Treatment of the blood-brain barrier with ibuprofen

ABSTRACT

A process for treating the blood-brain barrier by the systemic administration of ibuprofen (p-isobutylhydratropic acid) or a salt or ester thereof. Dosage forms are also disclosed.

DESCRIPTION

1. BRIEF DESCRIPTION OF THE INVENTION

This invention is the new use for known compounds, ibuprofen(p-isobutylhydratropic acid) including the salts or esters thereof, havebeen found to be useful for treatment of the blood-brain barrier by thesystemic administration of the compounds.

2. BACKGROUND OF THE INVENTION

Ibuprofen, its salt or esters, are known to be useful for treating avariety of medical conditions, including inflammation, arthritis, dentalpain, reducing platelet adhesiveness and in coronary infarct.

The blood-brain barrier (BBB) is a lipid membrane located between theplasma and the fluids of the brain. The BBB is a permeable membrane andis molecule selective. The BBB can be damaged and become dilated mainlydue to trauma, infection, shock, and irradiation resulting in edema andallowing passage of compounds such as drugs, bacteria, virus and thelike which would otherwise not pass from the blood to the brain.

DETAILED DESCRIPTION OF THE INVENTION

The active compounds of the present invention are ibuprofen(p-isobutylhydratropic acid) including the alkyl esters of from 1 to 8carbon atoms, inclusive, including isomeric forms or thepharmacologically acceptable salts.

The esters can be the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, and octyl esters.

Pharmacologically acceptable salts can be, for example, the alkalimetal, alkaline earth and ammonium salts.

The compositions of the present invention are preferably presented forsystemic administration to humans and animals in unit dosage forms, suchas tablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile nonparenteral solutions orsuspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient.

For oral administration either solid or fluid unit dosage forms can beprepared.

Powders are prepared quite simply by comminuting the active ingredientto a suitably fine size and mixing with a similarly comminuted diluent.The diluent can be an edible carbohydrate material such as lactose orstarch. Advantageously, a sweetening agent or sugar is present as wellas a flavoring oil.

Capsules are produced by preparing a powder mixture as hereinafterdescribed and filling into formed gelatin sheaths. Advantageously, as anadjuvant to the filling operation, a lubricant such as talc, magnesiumstearate, calcium stearate and the like is added to the powder mixturebefore the filling operation.

Soft gelatin capsules are prepared by machine encapsulation of a slurryof active ingredients with an acceptable vegetable oil, light liquidpetrolatum or other inert oil or triglyceride.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing an active ingredient, suitably comminuted, with adiluent or base such as starch, lactose, kaolin, dicalcium phosphate andthe like. The powder mixture can be granulated by wetting with a bindersuch as corn syrup, gelating solution, methylcellulose solution oracacia mucilage and forcing through a screen. As an alternative togranulating, the powder mixture can be slugged, i.e., run through thetablet machine and the resulting imperfectly formed tablets broken intopieces (slugs). The slugs can be lubricated to prevent sticking to thetablet-forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets.

Advantageously, the tablet can be provided with a protective coatingconsisting of a sealing coat or enteric coat of shellac, a coating ofsugar and methylcellulose and a polish coating of carnauba wax.

Fluid unit dosage forms for oral administration such as syrups, elixirsand suspensions can be prepared wherein each teaspoonful of compositioncontains a predetermined amount of active ingredient for administration.The water-soluble forms can be dissolved in an aqueous vehicle togetherwith sugar, flavoring agents and preservatives to form a syrup. Anelixir is prepared by using a hydroalcoholic vehicle with suitablesweeteners together with a flavoring agent. Suspensions can be preparedof the insoluble forms with a suitable vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing an active ingredient and a sterile vehicle, water beingpreferred. The active ingredient, depending on the form andconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the water-soluble active ingredient can bedissolved in water for injection and filter sterilized before fillinginto a suitable vial or ampule and sealing. Advantageously, adjuvantssuch as a local anesthetic, preservative and buffering agents can bedissolved in the vehicle. Parenteral suspensions are prepared insubstantially the same manner except that an active ingredient issuspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The active ingredient can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of theactive ingredient.

In addition to oral and parenteral administration, the rectal andvaginal routes can be utilized. An active ingredient can be administeredby means of a suppository. A vehicle which has a melting point at aboutbody temperature or one that is readily soluble can be utilized. Forexample, cocoa butter and various polyethylene glycols (carbowaxes) canserve as the vehicle.

The term "unit dosage form" as used in the specification and claimsrefers to physically discrete units suitable as unitary dosages forhuman and animal subjects, each unit containing a predetermined quantityof active material calculated to produce the desired therapeutic effectin association with the required pharmaceutical diluent, carrier orvehicle. The specifications for the novel unit dosage forms of thisinvention are dictated by and are directly dependent on (a) the uniquecharacteristics of the active material and the particular therapeuticeffect to be achieved, and (b) the limitation inherent in the art ofcompounding such an active material for therapeutic use in humans, asdisclosed in this specification, these being features of the presentinvention. Examples of suitable unit dosage forms in accord with thisinvention are tablets, capsules, troches, suppositories, powder packets,wafers, cachets teaspoonfuls, tablespoonfuls, dropperfuls, ampules,vials, segregated multiples of any of the foregoing, and other forms asherein described.

The systemic administration of ibuprofen, its salts or esters, to humansor animals provides a useful method of treating a damaged blood-brainbarrier. Human or animal subjects who have an injured blood-brainbarrier due to trauma, infection, shock, or an irradiation can beadministered the compounds to restore the blood-brain barrier to itshealthy function.

The dose of ibuprofen, its salts or esters, for treating the blood-brainbarrier is the same dose known for treating conditions for which it ispreviously known to be useful. In general, from about 2.5 mg to about 50mg per kilogram body weight administered daily in single or divideddosage amount.

The following examples are illustrative of the present invention, butare not intended to be limiting.

EXAMPLE 1 Hard Gelatin Capsules

One thousand two-piece hard gelatin capsules for oral use, each capsulecontaining 100 mg of ibuprofen are prepared from the following types andamounts of ingredients:

Ibuprofen: 100 gm

Lactose: 100 gm

Corn starch: 20 gm

Talc: 20 gm

Magnesium stearate: 2 gm

The ibuprofen (finely divided by means of an air micronizer) is added tothe other finely powdered ingredients, mixed thoroughly and thenencapsulated in the usual manner.

The foregoing capsules are useful for treating a damaged blood-brainbarrier due to a virus infection by the oral administration of twocapsules four times a day.

Using the procedure above, capsules are similarly prepared containingibuprofen in 300, 400, and 600 mg amounts by substituting 300, 400, and600 gm of ibuprofen for the 100 gm used above.

EXAMPLE 2 Soft Gelatin Capsules

One-piece soft gelatin capsules for oral use, each containing 300 mg ofibuprofen (finely divided by means of an air micronizer) are prepared byfirst suspending the compound in 0.5 ml of corn oil to render thematerial capsulatable and then capsulating in the above manner.

The foregoing capsules are useful for treating cerebral edema due to atraumatized blood-brain barrier by the oral administration of twocapsules four times a day.

EXAMPLE 3 Tablets

One thousand tablets, each containing 300 mg of ibuprofen are preparedfrom the following types and amounts of ingredients:

Ibuprofen micronized: 300 gm

Lactose: 75 gm

Corn starch: 50 gm

Magnesium stearate: 4 gm

Light liquid petrolatum: 5 gm

The ibuprofen (finely divided by means of an air micronizer) is added tothe other ingredients and then thoroughly mixed and slugged. The slugsare broken down by forcing through a number sixteen screen. Theresulting granules are then compressed into tablets, each tabletcontaining 300 mg of ibuprofen.

The foregoing tablets are useful for treating a damaged blood-brainbarrier due to a virus infection by the oral administration of one ortwo tablets four times a day.

Using the procedure above, tablets are similarly prepared containingibuprofen in 400 mg and 600 mg amounts by substituting 400 gm and 600 gmof ibuprofen for the 300 gm used above.

EXAMPLE 4 Oral Suspension

One thousand ml of an aqueous suspension for oral use, containing ineach teaspoonful (5 ml) dose, 100 mg of ibuprofen, aluminum salt isprepared from the following types and amounts of ingredients:

Ibuprofen, Aluminum Salt micronized: 20 gm

Citric acid: 2 gm

Benzoic acid: 1 gm

Sucrose: 700 gm

Tragacanth: 5 gm

Lemon oil: 2 gm

Deionized water, q.s.: 1000 ml

The citric acid, benzoic acid, sucrose, tragacanth and lemon oil aredispersed in sufficient water to make 850 ml of suspension. Theibuprofen aluminum salt (finely divided by means of an air micronizer)is stirred into the syrup until uniformly distributed. Sufficient wateris added to make 1000 ml.

The composition so prepared is useful for treating a damaged blood-brainbarrier resulting from irradiation at a dose of one tablespoonful (15ml) four times a day.

EXAMPLE 5

A sterile aqueous solution for parenteral (i.v.) injection, containingin one liter, 350 mg of ibuprofen, sodium salt is prepared from thefollowing types and amounts of ingredients:

Ibuprofen sodium salt: 350 mg

Water for injection, q.s.: 1000 ml

To the sterile solution is added sterilized ibuprofen, sodium salt andfilled into sterile containers sealed.

The composition so prepared is useful for treating a damaged blood-brainbarrier due to an encephalitis infection at a dose of one liter everyeight hours.

EXAMPLE 6

Following the precedure of the proceeding Examples 1 through 5,inclusive, compositions are similarly prepared substituting equimolaramounts of the ester, e.g., methyl, ethyl, isopropyl, octyl, or salt,e.g., sodium, potassium, ammonium, for the compound of the examples.

We claim:
 1. A process for therapeutic treatment of the blood-brainbarrier comprising the systemic administration to a human or animalhaving a damaged blood-brain barrier of an effective amount ofp-isobutylhydratropic acid or an alkyl ester of from 1 to 8 carbonatoms, inclusive, including isomeric forms thereof, or apharmacologically acceptable salt thereof.
 2. The process of claim 1wherein the compound is p-isobutylhydratropic acid.